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She started her career as a child model with Wilhelmina Models before turning her attention to acting, making her film debut in That Night (1992) and later appearing in My Father the Hero (1994) as well as Under Siege 2: Dark Territory (1995). Heigl then landed the role of Isabel Evans on The WB television series Roswell (1999–2002), for which she received nominations for Saturn and Teen Choice Awards.

She then starred in commercially successful romantic comedy films such as Knocked Up (2007), 27 Dresses (2008), The Ugly Truth (2009), Killers (2010), Life As We Know It (2010) and New Year's Eve (2011). She also appeared in Zyzzyx Road (2006), The Big Wedding (2013), and Unforgettable (2017). Heigl has also starred in several films that have seen limited releases, including Jackie & Ryan (2014), Home Sweet Hell (2015), and Jenny's Wedding (2015).

She is also executive producer on her leading television roles, which include the short-lived NBC television series State of Affairs from 2014 to 2015, the Netflix series Firefly Lane (2021–present) and the upcoming limited series Woodhull. She has also lent her voice to the animated film The Nut Job (2014) and its 2017 sequel. Heigl also had a main role in the final two seasons of the USA Network series Suits (2018–2019).